It has been demonstrated that the intimal fibromuscular lesion (IFML) or neointimal fibroplasia, is the lesion responsible for the late failure of at least 50% of all failed human arterial reconstructions and that this lesion is hemodynamically determined. The IFML also is believed by investigators to be a precursor of atherosclerotic plaque. Based upon the study of failed human arterial reconstructions, an in vivo experimental model for the rapid, hemodynamic induction of IFML in dog arteries has been developed. The early pathogenesis of this lesion has been extensively studied in this model, leading to identification of a limited number of possible initiating factors. The IFML often develops in this model at sites showing a full and apparently normal endothelial lining. The goals of the present proposal are to exploit this hemodynamic model in order to: 1) further test the theory that endothelial damage is the key initiating factory in the pathogenesis of the IFML through the use of tracer molecules to demonstrate subtle changes in endothelial permeability, 2) correlate size and severity of IFML with certain measured and calculated physiological parameters, 3) Learn the relative roles of 4 isolated components of flowing blood in causing and promoting the IFML by means of controlled perfusion of the model with a variety of pumped specific fluids, 4) ascertain the role, if any, of SMC mitosis in growth of IFML and identify stem cell and mechanisms of intimal invasion through application of mitostatic drugs to the rapid model, 5) further develop the method of analyzing audible signals emitted at vascular site of rapid flow to predict if IFML will develop at that site, and 6) determine if high lipid diets given to euthyroid dogs in whom the hemodynamic model has been prepared result in converting the hemodynamically induced IFML into atherosclerotic plaque. The ultimate goal is to identify key initiating factors in pathogenasis of IFML, where and how to interdict lesion, and thereby increase long-term patency of arterial reconstructions and possiblt block formation of atherosclerotic plaque.